A Phase I Dose-Finding Study Of Sorafenib (S) In Combination With Gemcitabine (G) And Radiotherapy (Rt) In Patients (Pts) With Unresectable Pancreatic Carcinoma (Upc): A Gemcad Study

e14525 Background: Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-beta, has activity against pancreatic cancer in pre-clinical models. Due to the radio-sensitization activity of S and G we designed a phase I multi-center trial to evaluate the safety and efficacy of this combination with concomitant RT. Methods: Pts with biopsy-proven UPC, based on spiral CT vascular invasion, were treated with G 300 mg/m2 iv weekly (QW) x 5 weeks concurrently with RT (45 Gy) in 25 fractions and S in a dose escalated in a ‘‘3+3’’ design from 200mg QD, 400 mg QD and 400 mg BID. Radiation portals included the primary tumor alone, without inclusion of regional lymph nodes. Pts with planning target volume (PTV) over 500 cc were excluded. Pts not progressing during chemo-RT were allowed to receive S till progression. Results: 12 pts were enrolled. Three pts received 200mg QD, six pts 400mg QD and three pts 400mg BID. The median age was 59 years (range 39-69), 5 male, ECOG PS 0/1 (1/11). No DLTs occurred. The most common grade 2 toxicities were fatigue (4), neutropenia (3), nausea (5), and transaminitis (4). Treatment was discontinued in one patient because reversible posterior leukoencephalopathy. No other pts required admission due to therapy. There were no toxic deaths. PTV ranged between 105-500cc. All pts were evaluable for response with 2 objective partial responses and 7 SD. Median progression free-survival and overall survival were 4.4 (95% CI 3.4-5.4) and 10 months (95% CI 5.7-14.3), respectively. Conclusions: The addition of S to G-RT without prophylactic nodal irradiation, demonstrated a safe toxicity profile and modest activity in UPC.